Radiation Induced Cystitis Treated With Hyperbaric Oxygen - A Randomized Controlled Trial (RICH-ART)

The primary objective of this study is to assess the relief of symptoms after Hyperbaric Oxygen Therapy (HBOT) in patients with late radiation cystitis by having Expanded Prostate cancer Index Composite (EPIC)symptom estimation scale as primary variable.

Study hypothesis:

• HBOT can reduce or reverse the change or otherwise limit the damage of the bladder function and/or structure, which arose as a result of radiation therapy of cancer in the pelvic region organs.
• The effects of HBOT are associated with relief of symptoms that, at least in part, is related to the reduction of the extent of the radiation damage.
• Vascular density increases, fibrosis prevalence and inflammatory activity are reduced as a sign of an improved function of the mucosa.
• Treatment results of HBOT remains, in whole or in part, during the follow-up (residual effect)

Study Overview

• Status: Completed
• Conditions: Cystitis, Radio Induced
• Intervention / Treatment: Drug: Hyperbaric Oxygen

Detailed Description

Radiotherapy is commonly used in the management of malignant diseases. Despite a continuous improvement of the technique, with improved efficacy and tolerance, adverse effects are still rather common. The urinary bladder and rectum are the major organs most commonly affected by radiotherapy to the pelvis area.

One of the most significant causes of the symptoms of radio therapy is inflammation and degeneration of blood vessels in the radiated tissue. Hyperbaric oxygen therapy involves administration of oxygen at greater than normal atmospheric pressures. A well-documented effect of HBOT is the stimulation of angiogenesis. HBOT is an established treatment for degeneration of blood vessels in the jaw bone as a result of radiotherapy and several publications have shown good efficacy also when soft tissue is affected.

If the method of treatment with HBOT means a reduction of the radiotherapy side effect it is thus an obvious importance for the individual patient. There is also significant potential savings for the healthcare and society.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet Copenhagen
• Finland
  • Turku, Finland
    • Turku hospital
• Norway
  • Bergen, Norway
    • Haukeland Universitetssykehus
• Sweden
  • Gothenburg, Sweden
    • Shalgrenska University Hospial
  • Stockholm, Sweden
    • Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures
• Female or male aged 18-80 years
• Intended curative radiation of the pelvic region as a treatment for cancer
• End of radiation therapy more than 6 months ago
• Radiation cystitis with Urological EPIC < 80
• Radiation cystitis is the most probable cause for the patient's symptoms

Exclusion Criteria:

• Patients with major and ongoing bleedings from the bladder (requiring more than 0.5L blood-transfusion within the last four weeks)
• Refractory incontinence requiring catheter or surgical intervention
• Urine bladder capacity < 100ml
• Fistula in the urine bladder
• Contraindications for HBOT according to the local centres routines
• Pregnancy
• Mechanical ventilator support
• Unable to follow and understand simple commands
• Not oriented to person, place and time

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: A - Immediate start; Start of treatment within 6 weeks of inclusion in the study. 100% oxygen at 240-250 kPa will be delivered to the patents for 80-90 minutes while sitting or lying in a hyperbaric oxygen chamber. Patients will receive treatment once every day, except week-ends, for 40 days.	Drug: Hyperbaric Oxygen; 100% oxygen at 240-250 kPa will be delivered to the patents for 80-90 minutes while sitting or lying in a hyperbaric oxygen chamber. Patients will receive treatment once every day, except week-ends, for 40 days.
NO_INTERVENTION: B - delayed start; Delayed start: Start of treatment not before 6 months of inclusion in the study. No intervention is given during the initial period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EPIC (Expanded Prostate cancer Index Composite)	EPIC was developed to measure health-related quality of life among men with prostate cancer (22) modified to enhance sensitivity to therapy effects. It comprises four summary domains; urinary, bowel, sexual and hormonal. The primary objective of this study is to assess the relief of symptoms after HBOT in patients with late radiation cystitis by having EPIC symptom estimation scale as primary variable, comparing results between group A (post treatment) and group B (pre treatment). All patients (Group A and B) will complete EPIC and SF-36 in a post-study long-term follow-up. This is done yearly for 5 years (18, 30, 42, 54 and 66 months post inclusion).	At inclusion, 6 months after inclusion (i.e. post treatment for group A and pre treatment for group B) and for long-term follow-up as specified under "description"

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microscopic assessment	To investigate the mucosa with respect to functionality by assessment of inflammation activity, quantification of fibrosis, vascular density and the presence of stems cells having histological analysis from biopsies as variable. Comparison will be made between group A (post treatment) and group B (pre treatment)	At inclusion and 6 months after inclusion (i.e. post treatment for group A and pre treatment for group B)
RTOG (Radiation Toxicity Grade by Radiation Therapy Oncology Group)	RTOG is an internationally well established research group in the oncology field. They have developed organ specific scales for quantification of both acute and late symptoms after radiation. The scale range is from 0 to 5, where 0 is used for normal function and findings and 5 for death directly related to injuries post radiation. Both subjective and objective findings are used when setting the score. Comparison will be made between Group A (post treatment) and Group B (pre treatment)	At inclusion and 6 months after inclusion (i.e. post treatment for group A and pre treatment for group B)
SF-36 (Short Form Health Survey 36)	SF-36 is a self-administered questionnaire and contains 36 items which measure eight dimensions and assess health-related quality of life. Comparing results between Group A (post treatment) and Group B (pre treatment). All patients (Group A and B) will complete EPIC and SF-36 in a post-study long-term follow-up. This is done yearly for 5 years (18, 30, 42, 54 and 66 months post inclusion).	At inclusion, 6 months after inclusion (i.e. post treatment for group A and pre treatment for group B) and for long-term follow-up as specified under "description"
Adverse events	Adverse events (AE) are recorded during HBOT and Serious adverse events (SAE) until visit 4.	Every day during HBOT (8 weeks).

Collaborators and Investigators

• Sponsor: Göteborg University
• Collaborators: Sahlgrenska University Hospital, Sweden
• Investigators: Principal Investigator: Nicklas Oscarsson, MD, Sahlgrenska, Gothenburg University

Publications and helpful links

General Publications

• Oscarsson N, Muller B, Rosen A, Lodding P, Molne J, Giglio D, Hjelle KM, Vaagbo G, Hyldegaard O, Vangedal M, Salling L, Kjellberg A, Lind F, Ettala O, Arola O, Seeman-Lodding H. Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2-3 trial. Lancet Oncol. 2019 Nov;20(11):1602-1614. doi: 10.1016/S1470-2045(19)30494-2. Epub 2019 Sep 16. Erratum In: Lancet Oncol. 2019 Sep 23;:

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (ACTUAL): August 9, 2018
• Study Completion (ACTUAL): August 9, 2018

Study Registration Dates

• First Submitted: August 2, 2012
• First Submitted That Met QC Criteria: August 3, 2012
• First Posted (ESTIMATE): August 8, 2012

Study Record Updates

• Last Update Posted (ACTUAL): June 26, 2019
• Last Update Submitted That Met QC Criteria: June 24, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Hyperbaric Oxygen; Urinary bladder; Radio therapy; STRI
• Additional Relevant MeSH Terms: Urologic Diseases; Urinary Bladder Diseases; Cystitis
• Other Study ID Numbers: RICH-ART 2012-001381-15; 2012-001381-15 (EUDRACT_NUMBER)